Abstract Ultraviolet B radiation (UVB) is an environmental carcinogen, which is one of the major causative factors of skin cancer formation. Activation of NF-kB has been shown to play an important role in carcinogenesis by inhibiting apoptosis and therefore enhancing cell transformation. Thus, the NF-kB signaling network has been a major target for development of therapeutics for prevention of UVB-induced skin carcinogenesis. We reported a non-canonical pathway for activation of NF-kB that is mediated by constitutive nitric oxide synthase (cNOS) in the early phase (6 h) after UVB irradiation. At the same time, activation of cNOS is expected to promote cell damage by producing toxic peroxynitrite (ONOO?) from nitric oxide (NO?) and superoxide (O2??). Therefore, UVB-induced activation of cNOS promotes skin carcinogenesis by increasing the extent of DNA damage, decreasing the capacity of DNA damage repair and promoting the survival of damaged cells. This finding suggests that cNOS inhibitors could protect against development of skin cancer via blocking the synergistic effect of DNA damage and anti-apoptotic activity of NF-kB. A desirable property of cNOS as a target is that it only affects UVB-induced but not TNFa-induced NF-kB activation. The objective of this proposal is to elucidate the fundamental molecular mechanism of UVB-induced skin carcinogenic responses through a detailed study of cNOS-coordinated pro-death oxidative/nitrosative stress and DNA damage as well as pro-survival NF-kB activation and autophagy induction. The innovation of this proposal resides on the novel hypotheses that UVB-induced early phase NF-kB activation is solely dependent on cNOS activation; and cNOS is a promising potential target for chemoprevention of UVB-induced skin carcinogenesis. This hypothesis is based on the oncogenic properties of cNOS in causing DNA damage, activating NF-kB, and inducing autophagy via NF-kB-regulated stabilization of IKKa. In addition, the proposed mechanism for regulation and the functional role of NF-kB-IKKa signaling cascade is a novel conceptual ?reversal? of the normal IKKa-NF-kB signaling. The therapeutic use of cNOS inhibitors in preventing UVB-induced DNA damage, cell death, as well as skin carcinogenesis is clinically innovative. The proposed study can potentially lead to the development of new therapeutics for chemoprevention and treatment of UVB-induced skin cancer.